Novel polymorphs and salts

ABSTRACT

Novel polymorphic forms and salts of 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid are useful for the prevention or treatment of Alzheimer&#39;s Disease.

CROSS REFERENCES TO RELATED APPLICATIONS

This claims priority to European Patent Application No. 10158954.7,filed on Apr. 1, 2010, which is incorporated herein by reference in itsentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to new crystalline forms and salts of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid ofthe following formula:

The present invention also relates to methods for the prevention andtreatment of medical conditions such as Alzheimer's Disease and otherforms of dementia by administering such a crystalline form or salt.

2. Discussion of the Background

Alzheimer's Disease is a devastating neurological disorder affectingmore than 37 million people worldwide. As yet, there are no approveddrugs capable of preventing or reversing the disease. A particular focusof research and development efforts is on preventing formation ofsynaptotoxic (β-amyloid (Aβ) peptide in the brain and its aggregationinto plaques.

The gamma secretase modulator compound1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid wasfirst described in patent application WO 2004/074232 as one of a largenumber of candidate therapeutic agents for neurodegenerative diseasessuch as Alzheimer's disease. That application does not disclose anycrystal forms or specific salts of the compound.

Polymorphism is defined as the ability of a substance to crystallize inmore than one crystal lattice arrangement. Polymorphism can influencemany aspects of solid state properties of a drug. Different crystalmodifications of a substance may differ considerably from one another inmany respects, such as their solubility, dissolution rate andbioavailability.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelpolymorphs of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid.

It is another object of the present invention to provide novel saltforms of 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylicacid.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat that 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylicacid can exist in multiple crystalline polymorphic forms. Furthermore,it has been possible to prepare a selection of novel salts of thecompound. These new polymorphs and salt forms are particularly useful inthe preparation and further development of effective therapies forAlzheimer's disease.

Thus, the present invention provides a first novel polymorphic form of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid,termed Form I.

The present invention further provides a second polymorphic form of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid,termed Form II.

In a further aspect the present invention provides a third polymorphicform of 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylicacid, termed Form III.

In another aspect the present invention provides salts of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acidselected from the group consisting of: Na, K, Ca, L-Arginine,D-Arginine, and L-Lysine salts.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising any of the novel polymorphic or salt forms of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid ofthe invention, and a pharmaceutically acceptable carrier.

In yet another aspect, the present invention provides a method forpreventing or treating a neurodegenerative disease in a patient,comprising administering an effective amount of a polymorphic form of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid, ora salt of 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylicacid selected from the group consisting of: Na, K, Ca, L-Arginine,D-Arginine, and L-Lysine salts.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same become betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 shows the X-ray diffraction pattern (XRDP) of polymorph Form I of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid;

FIG. 2 shows the XRDP of polymorph Form II of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid;

FIG. 3 shows the XRDP of polymorph Form III of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid; and

FIG. 4 shows the XRDP of the L-Lysine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It has now been found that1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid canexist in multiple crystalline polymorphic forms, three of which arestable and have been identified and are characterized in the Examples.The term “crystalline polymorph” refers to a crystal modification thatcan be characterized by analytical methods such as X-ray powderdiffraction (XRPD) and Infra-Red (IR)-spectroscopy, or by its meltingpoint (for instance, as measured by Differential Scanning calorimetry,DSC).

In a first aspect the invention relates to crystalline polymorph Form Iof the compound of Formula I:

i.e., that form characterized by an XRPD pattern having characteristicpeaks expressed in angle 2-theta at approximately those values shown inTable 1.

TABLE 1 Degrees 2-theta 17.02 19.29 20.44 23.67 25.58 30.03

When used with reference to XRPD peaks, the term “approximately” meansthat there is an uncertainty in the measurements of the degrees 2-theta(2θ) of ±0.2° (expressed in degrees 2-theta).

In another embodiment, the Form I crystalline polymorph is characterizedby an XRPD pattern comprising characteristic peaks with approximate 2θvalues as indicated in Table 2, and with relative intensities deviatingby no more than ±30%, preferably no more than ±10% from the values givenin Table 2.

TABLE 2 Degrees 2-theta Relative intensity (%) 17.02 100.0 19.29 68.820.44 52.3 23.67 57.0 25.58 60.6 30.03 46.5

In another embodiment, the Form I crystalline polymorph is characterizedby an XRPD pattern comprising characteristic peaks with approximate 2θvalues as indicated in Table 3.

TABLE 3 Diffraction Angle (°2θ) 16.63 17.02 19.29 20.44 22.46 23.6725.00 25.58 26.34 26.63 28.24 28.66 30.03 30.24 32.58

The Form I polymorph can also be defined as having an XRPD patternhaving characteristic peaks and relative intensities substantially asillustrated in FIG. 1.

Furthermore, the Form I crystalline polymorph can be characterized byits melting point. Therefore, the invention also encompasses a Form Icrystalline polymorph of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acidhaving a melting temperature onset at about 200° C. and peaking at about202° C. (as measured, for instance, by DSC).

In a second aspect, the invention relates to crystalline polymorph FormII of the compound of Formula I, namely that form characterized by anXRPD pattern having characteristic peaks expressed in angle 2-theta atapproximately those values shown in Table 4.

TABLE 4 Degrees 2-theta 17.22 19.14 19.23 20.34 24.17 25.02

In another embodiment, the Form II crystalline polymorph ischaracterized by an XRPD pattern comprising characteristic peaks withapproximate 2θ values as indicated in Table 5, and with relativeintensities deviating by no more than ±30%, preferably no more than ±10%from the values given in Table 5.

TABLE 5 Degrees 2-theta Relative intensity (%) 17.22 92.8 19.14 84.519.23 100.0 20.34 72.7 24.17 69.7 25.02 85.4

In another embodiment, the Form II crystalline polymorph ischaracterized by an XRPD pattern comprising characteristic peaks withapproximate 2θ values as indicated in Table 6.

TABLE 6 Diffraction Angle (°2θ) 16.41 17.09 17.22 17.78 19.14 19.2320.34 21.98 24.17 24.76 25.02 25.88 26.11 28.00 28.52 28.95 29.21 29.9930.82

The Form II polymorph can also be defined as having an XRPD patternhaving characteristic peaks and relative intensities substantially asillustrated in FIG. 2.

Furthermore, the Form II crystalline polymorph can be characterized byits melting point. Therefore, the invention also encompasses acrystalline polymorph of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acidhaving a melting temperature onset at about 200° C. and peaking at about202° C.

In a third aspect the invention relates to Form. III of the compound ofFormula I, namely that form characterized by an XRPD pattern havingcharacterized peaks expressed in angle 2-theta at approximately thosevalues shown in Table 7.

TABLE 7 Degrees 2-theta 19.37 19.46 20.45 20.64 23.97 24.16

Preferably the Form III crystalline polymorph is characterized by anXRPD pattern comprising characteristic peaks with approximate 20 valuesas indicated in Table 8, and with relative intensities deviating by nomore than ±30%, preferably no more than ±10% from the values given inTable 8.

TABLE 8 Degrees 2-theta Relative intensity (%) 19.37 15.0 19.46 21.820.45 19.6 20.64 100.0 23.97 39.2 24.16 43.8

In another embodiment, the Form III crystalline polymorph ischaracterized by an XRPD pattern comprising characteristic peaks withapproximate 2θ values as indicated in Table 9.

TABLE 9 Diffraction Angle (°2θ) 19.37 19.46 20.45 20.64 23.97 24.1629.50 29.97

The Form III polymorph can also be defined as having an XRPD patternhaving characteristic peaks and relative intensities substantially asillustrated in FIG. 3.

Furthermore, the Form III crystalline polymorph can be characterized byits melting point. Therefore, the invention also encompasses acrystalline polymorph of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acidhaving a melting temperature onset at about 198° C. and peaking at about200° C.

The present invention encompasses polymorphs of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acidisolated in substantially pure form or when admixed with othersubstances, such as pharmaceutical excipients and/or therapeutic agents.A “substantially pure” isolated polymorph refers to a sample in whichthe polymorph is present in a substantial excess over other polymorphsof the same compound, i.e. in an amount exceeding 75%, more preferablyexceeding 90%, even more preferably exceeding 95%, and most preferablyexceeding 99% by weight of the total weight of the compound of Formula Iin the sample.

The present invention also provides processes for preparing thepolymorphs of the invention. Form I can be prepared under a variety ofconditions, as shown in the Examples. In general terms, the compound ofFormula I is dissolved in a suitable solvent, filtered, and then left toevaporate. Preferred solvents (depending on the recrystallizationconditions) include 1,2-dimethoxy ethane, 1-butanol, 2-methoxy ethanol,acetone, acetonitrile, chloroform, dichloromethane, diethyl ether,dioxane, DMF, DMSO, ethanol, ethyl acetate, methanol, nitromethane,1-propanol, and p-xylene. The recrystallization is preferably carriedout at room temperature.

According to one method of preparing the polymorphic Form II of thecompound of Formula I, the compound is first dissolved in dioxane,filtered, and then left to evaporate at room temperature.

According to one method of preparing the polymorphic Form III of thecompound of Formula I, the compound is first dissolved in acetone,filtered, and then left to evaporate at room temperature.

As described in the Examples, attempts were made to prepare salts of thecompound of Formula I using various different bases. Salts with Na, K,Ca, and with the basic amino acids L-Arginine, D-Arginine and L-Lysinewere successfully prepared, but attempts to manufacture salts using thebases piperazine, morpholine, betaine, choline, imidazole, magnesiumhydroxide and ammonia failed.

The Na, K, L-Arg and L-Lys salts of the present invention were testedand shown to have excellent solubility in water. Furthermore, thesesalts were found to have good stability when stored under conditions ofhigh humidity. The preferred salts of the invention are the Arginine andLysine salts of the compound of Formula I, because of the potentiallyharmful effects of administering the other salts in high dosages topatients having hypertension associated with Alzheimer's disease.

The present invention encompasses salts of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acidisolated in substantially pure form or when admixed with othersubstances, such as pharmaceutical excipients and/or therapeutic agents.A “substantially pure” isolated salt refers to a sample in which thesalt is present in a substantial excess over other salts or free base ofthe same compound, i.e. in an amount exceeding 75%, more preferablyexceeding 90%, even more preferably exceeding 95%, and most preferablyexceeding 99% by weight of the total weight of the salts and free baseof compound of Formula I in the sample.

The L-Lysine salt of the compound of Formula I has been recrystallizedand has been shown to adopt a Form I structure (FIG. 4). Thus, theinvention also relates to polymorphic Form I of the L-Lysine salt, and amethod for manufacturing the L-Lysine Form I polymorph comprisingdissolving the salt in ethanol, methanol or water, filtering theresulting solution, and allowing the solution to evaporate at roomtemperature.

The present invention also provides pharmaceutical compositionscomprising a polymorph or salt according to the invention, and one ormore pharmaceutically acceptable carriers or excipients, such ascarriers, diluents, wetting agents, emulsifying agents, binders,coatings, fillers, glidants, lubricants, disintegrants, preservatives,stabilizers, surfactants, pH buffering substances, flavouring agents andthe like. Comprehensive guidance on pharmaceutical excipients is givenin Remington's Pharmaceutical Sciences Handbook, XVII Ed. Mack Pub.,N.Y., U.S.A, which is incorporated herein by reference in its entirety.

In one embodiment, pharmaceutical compositions of the present inventioncomprise a crystalline polymorph or salt of the compound of Formula I incombination with one or more other therapeutically active substances, inparticular any pharmaceutical substance used for prevention or treatmentof Alzheimer's Disease.

The pharmaceutical compositions of the present invention may beformulated for administration by any convenient route, e.g. by oral,parenteral, topical, inhalation, buccal, nasal, rectal, vaginal,transdermal administration. Suitable dosage forms can include tablets,capsules, lozenges, suppositories, solutions, emulsions, suspensions,syrups, ointments, creams, oils, and powders. Preferably, thepharmaceutical compositions of the invention will be administered orallyusing appropriate dosage forms, such as capsules or tablets.

The dosage of the compounds of Formula I and their salts can vary withinwide limits depending on the nature of the disease to be treated, thetype of patient, and the mode of administration. A person skilled in theart can determine a therapeutically effective amount for each patientand thereby define the appropriate dosage. A typical daily dosage mightfall within the range of 400 mg to 800 mg, administered in a single ormultiple daily dosage units. Thus, a single dose of the pharmaceuticalpreparations of the invention conveniently comprises between about 100and 800 mg of a polymorph or salt of the compound of Formula I.

The polymorphs and salts of the present invention may be of use in thetreatment or prophylaxis of any disease or condition where it isadvantageous to modulate gamma secretase activity. In particular, thesesubstances may be useful in preventing or treating Alzheimer's disease.

Other embodiments of the invention include:

Polymorph Form I having characteristic XRPD peaks of relativeintensities of approximately:

Degrees 2-theta Relative intensity (%) 17.02 100.0 19.29 68.8 20.44 52.323.67 57.0 25.58 60.6 30.03 46.5

Polymorph Form I characterized in that it has a melting temperatureonset at about 200° C., and peaking at about 202° C.

Polymorph Form II, having characteristic XRPD peaks of relativeintensities of approximately:

Degrees 2-theta Relative intensity (%) 17.22 92.8 19.14 84.5 19.23 100.020.34 72.7 24.17 69.7 25.02 85.4

Polymorph Form II characterized in that it has a melting temperatureonset at about 200° C., and peaking at about 202° C.

Polymorph Form III having characteristic XRPD peaks of relativeintensities of approximately:

Degrees 2-theta Relative intensity (%) 19.37 15.0 19.46 21.8 20.45 19.620.64 100.0 23.97 39.2 24.16 43.8

Polymorph Form III characterized in that it has a melting temperatureonset at about 198° C., and peaking at about 200° C.

The compound1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid, atleast 70% of which is present as crystalline polymorph Form I.

The compound1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid, atleast 70% of which is present as crystalline polymorph Form II.

The compound1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid, atleast 70% of which is present as crystalline polymorph Form III.

Any of the polymorphs of the invention for use as a medicament.

A crystalline polymorph according to the invention for use in theprevention or treatment of Alzheimer's Disease.

A method of preventing or treating an amyloidogenic disease, such asAlzheimer's Disease, comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of a crystallinepolymorph of the invention.

A method of preparing crystalline Form I of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid,comprising dissolving the compound in an excess of solvent, filteringthe resulting solution, and allowing the solution to crystallize at roomtemperature, wherein the solvent is selected from the group consistingof: acetonitrile, chloroform, dichloromethane, diethyl ether, ethanol,ethyl acetate, methanol, and nitromethane.

A method of preparing crystalline Form II of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid,comprising dissolving the compound in an excess of dioxane, filteringthe resulting solution, and allowing the solution to crystallize at roomtemperature.

A method of preparing crystalline Form III of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid,comprising dissolving the compound in an excess of acetone, filteringthe resulting solution, and allowing the solution to crystallize at roomtemperature.

An L-Lysine, L-Arginine or D-Arginine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid.

A method of preparing crystalline Form I of the L-Lysine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid,comprising dissolving the salt in ethanol, methanol, or water; filteringthe resulting solution; and allowing the solution to evaporate at roomtemperature.

Crystalline Form 1 L-Lysine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acidcharacterized in that it provides an X-ray diffraction (XRPD) patternsubstantially in accordance with FIG. 4.

A salt according to the invention for use as a medicament.

A salt according to the invention for use in the prevention or treatmentof Alzheimer's Disease.

A method of preventing or treating an amyloidogenic disease, such asAlzheimer's Disease, comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of a salt of theinvention.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1 Identification of Novel Polymorphs: RecrystallizationExperiments 1.1. Room Temperature Recrystallization.

0.05 g of 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylicacid was dissolved in 4 mL of solvent with stirring. After about 1 hourof stirring the solution obtained was filtered through a Whatman filter(0.45 μm) and left to evaporate at room temperature for either 3 days or1 week. Table 10 shows the outcome of the recrystallization usingdifferent solvents. Polymorphic forms I, II and III were identified andcharacterized by XRPD and DSC.

XRPD analyses were performed using an X'Pert Pro instrument with a Cuanode and equipped with an X'Celerator (PANalytical, Netherlands) incontinuous scanning mode at 25° C., with a scan step size (° 2θ) of0.017 and a scan step time of 12.9 seconds. The characteristic XRPDspectra of Forms I, II and III are illustrated in FIGS. 1-3,respectively.

DSC analyses were carried out using a DCS Diamond instrument (PerkinElmer). Scan settings were 5° C./minute (PAN: open). Form I and Form IIcrystals were found to have a T_(onset) at about 200° C., the meltingtemperature peaking at about 202° C. Form III crystals had a T_(onset)of about 198° C., the melting temperature peaking at about 200° C.

TABLE 10 Solvent Result of RT crystallization attempt 1,2-dimethoxyethane Yield too low to characterize 1-butanol Yield too low tocharacterize 2-methoxy ethanol Yield too low to characterize acetoneForm III acetonitrile Form I c-hexane Yield too low to characterizechloroform Form I dichloromethane Form I diethyl ether Form I dioxaneForm II DMF Yield too low to characterize DMSO Yield too low tocharacterize ethanol Form I ethyl acetate Form I hexane Negative (lowsolubility) 1-propanol Yield too low to characterize iso-propyl etherYield too low to characterize methanol Form I methyl ethyl ketone Yieldtoo low to characterize nitromethane Form I p-xylene Negative (lowsolubility) t-butyl methyl ether Yield too low to characterizetert-butanol Yield too low to characterize THF Yield too low tocharacterize water Negative (low solubility)

1.2. Low Temperature Recrystallization.

0.05 g of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropane-carboxylic acid wasdissolved in 4 mL of solvent with stirring. After about 1 hour ofstirring the solution obtained was filtered through a Whatman filter(0.45 μm) and left to evaporate at 5° C. for 1-2 weeks. Table 11 showsthe outcome of the recrystallization using different solvents.Polymorphic forms I and II were identified and characterized by XRPD andDSC as described above.

TABLE 11 Solvent Result of low temperature crystallization attempt1,2-dimethoxy ethane Yield too low to characterize 1-butanol Yield toolow to characterize 2-methoxy ethanol Yield too low to characterizeacetone Form I acetonitrile Form I c-hexane Yield too low tocharacterize chloroform Form I dichloromethane Form I diethyl ether FormI dioxane Form I + Form II DMF Yield too low to characterize DMSO Yieldtoo low to characterize ethanol Form I ethyl acetate Form I hexaneNegative (low solubility) 1-propanol Yield too low to characterizeiso-propyl ether Yield too low to characterize methanol Form I methylethyl ketone Yield too low to characterize nitromethane Form I p-xyleneNegative (low solubility) t-butyl methyl ether Yield too low tocharacterize tert-butanol Yield too low to characterize THF Yield toolow to characterize water Negative (low solubility)

1.3. High Temperature Recrystallization.

0.05 g of 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylicacid was dissolved in 4 mL of solvent with stirring. After about 1 hourof stirring the solution obtained was filtered through a Whatman filter(0.45 μm) and left to evaporate at 60° C. for 2-3 weeks. Table 12 showsthe outcome of the recrystallization using different solvents.Polymorphic form I was identified and characterized by XRPD and DSC asdescribed above.

TABLE 12 Solvent Result of high temperature crystallization attempt1,2-dimethoxy ethane Form I 1-butanol Form I 2-methoxy ethanol Form Iacetone Yield too low to characterize acetonitrile Form I c-hexane Yieldtoo low to characterize chloroform Yield too low to characterizedichloromethane Yield too low to characterize diethyl ether Yield toolow to characterize dioxane Form I DMF Form I DMSO Form I ethanol Yieldtoo low to characterize ethyl acetate Yield too low to characterizehexane Negative (low solubility) 1-propanol Form I iso-propyl etherYield too low to characterize methanol Yield too low to characterizemethyl ethyl ketone Yield too low to characterize nitromethane Form Ip-xylene Form I t-butyl methyl ether Yield too low to characterizetert-butanol Yield too low to characterize THF Yield too low tocharacterize water Negative (low solubility)

1.4. Preparation of Slurries.

The suspensions were prepared by dissolving 0.05 g of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acidsolid in 2 mL of solvent. The suspensions were stirred for 1 month atroom temperature, filtered through Whatman 0.45 μm filters and measuredbefore the sample began to dry. The results are shown in Table 13.Polymorphic forms I and II were identified and characterised by XRPD andDSC as described above. In all cases where the compound was notcompletely soluble in the solvent, slurries yielded only Form I.

EXAMPLES TABLE 13 Solvent Result methanol Form I acetone Form Iacetonitrile Form I THF Form I isopropyl ether Form I toluene Form Iethyl acetate Form I 1-propanol Form I dioxane Form II p-xylene Form Imethyl ethyl ketone Form I 1-butanol Form I chloroform Form Idichloromethane Form I hexane Form I ethanol Form I nitromethane Form Iwater Form I TBME Form I c-hexane Form I diethyl ether Form IThe experiment was repeated, this time stirring the slurries for 7 daysat room temperature instead of 30 days. The crystallization results werethe same.

Example 2 Preparation and Characterization of Salts of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid 2.1.Salt Screening.

1.5×10⁻⁴ mol of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid(0.500 g) and 1.5×10⁻⁴ mol of base (summarized in Examples Table 5) wereadded to 5 ml water, and stirred at 500 rpm and 40° C. for 1 hour whilemonitoring the pH values. When the pH value was about 7, the solutionwas filtered and concentrated under vacuum. A pink powder was obtainedfor each salt. The results are shown in Table 14.

TABLE 14 Base Quantity Result Sodium hydroxide  0.06 g Salt obtainedPotassium hydroxide 0.084 g Salt obtained Calcium hydroxide 0.111 g Saltobtained L-Arginine 0.261 g Salt obtained L-Lysine 0.219 g No saltD-Arginine 0.261 g Salt obtained Piperazine 0.129 g No salt Morpholine0.130 g (d = 1, mL = 0.130) No salt Betaine 0.175 g No salt Choline0.181 g (d = 1.09; mL = 0.166) No salt Imidazole 0.102 g No saltMagnesium hydroxide 0.087 g No salt Ammonia 0.170 mL No salt

The experiment was then repeated with ethanol instead of water, usingthose bases that failed to yield a salt in the first experiment. Theresults are shown in Table 15.

TABLE 15 Base Quantity Result L-Lysine 0.219 g Salt obtained Choline0.181 g (d = 1.09; mL = 0.166) No salt Imidazole 0.102 g No saltMagnesium hydroxide 0.087 g No salt Ammonia 0.170 mL No salt

Each of the salts obtained was characterized by X-ray powder diffraction(XRPD), Thermogravimetric analysis (TGA), and Differential Scanningcalorimetry (DSC). Furthermore, the stabilities of the sodium,potassium, L-Arginine and L-Lysine salts were tested by storage for 7days at room temperature and 80% relative humidity. No changes were seenin the XRPD pattern.

2.2. Thermodynamic Solubility of Salts.

Each of the sodium, potassium, L-Arg and L-Lys salts prepared asdescribed above was dissolved in water at a temperature of 37° C., pH6.8-7.4 at a stirring rate of 500 rpm for 24 hours. The results areshown in Table 16.

TABLE 16 Salt Amount Volume of water Solubility g/L Sodium  81.5 mg 4 mL20.4 Potassium  12.6 mg 2 mL 6.3 L-Arginine  60.6 mg 4 mL 15.2 L-Lysine146.4 mg 4 mL 36.6These solubility values are predictive of good in vivo solubility.

2.3. Re-Crystallization of L-Lysine Salt.

The L-Lysine salt was dissolved in 4 mL of solvent with stirring. Afterabout 1 hour of stirring the solution obtained was filtered through aWhatman filter (0.45 μm) and left to evaporate at room temperature for 3days or 1 week. Table 17 shows the outcome of the recrystallization. Thecrystals were analysed by XRPD as described above. The recrystallizationof the L-Lysine salt in chloroform produced a sample having an identicaldiffraction pattern to that of the free base.

TABLE 17 Solvent Result of room temperature crystallization attempt1,2-dimethoxy ethane Yield too low to characterize 1-butanol Yield toolow to characterize 2-methoxy ethanol Yield too low to characterizeacetone Yield too low to characterize acetonitrile Yield too low tocharacterize c-hexane Yield too low to characterize chloroform =freebase dichloromethane Yield too low to characterize diethyl ether Yieldtoo low to characterize dioxane Yield too low to characterize DMF Yieldtoo low to characterize DMSO Yield too low to characterize ethanol FormI ethyl acetate Yield too low to characterize hexane Yield too low tocharacterize 1-propanol Yield too low to characterize iso-propyl etherYield too low to characterize methanol Form I methyl ethyl ketone Yieldtoo low to characterize nitromethane Yield too low to characterizep-xylene Yield too low to characterize t-butyl methyl ether Yield toolow to characterize tert-butanol Yield too low to characterize THF Yieldtoo low to characterize water Form I

An XRPD diagram of the L-Lysine form I salt is provided in FIG. 4. TheForm I salt is characterized by an XRPD pattern comprisingcharacteristic peaks with approximate 2θ values as indicated in theTable 18, and with relative intensities deviating by no more than ±30%,preferably no more than ±10% from the values given in Table 18.

TABLE 18 Degrees 2-theta Relative intensity (%) 7.09 21.7 17.25 28.119.40 100.0 20.95 29.6 21.58 29.8 26.85 25.3

When the experiment was repeated at recrystallization temperature of 5°C. for 1-2 weeks similar crystallization results were achieved.

When the experiment was repeated at a recrystallization temperature of60° C. for 2-3 days the only solvent yielding crystals was water (Form Icrystals).

Slurries were prepared by dissolving 0.050 g of the L-Lysine salt in 2mL of solvent. The suspensions were stirred for 7 days at roomtemperature, filtered through Whatman filters and measured before thesample began to dry. The crystals were analysed by XRPD as describedabove. The results are shown in Table 19 (C03=identical to free base):

TABLE 19 Solvent Result methanol Form I acetone Form I acetonitrile FormI ethyl acetate Form I 1-propanol Form I dioxane Form I p-xylene Form I1-butanol Form I chloroform Form I + C03 dichloromethane Form I hexaneForm I ethanol Form 1 nitromethane Form I water — 1,2-dimethoxy ethaneForm I c-hexane Form I diethyl ether Form I 2-methoxy ethanol Form I DMFForm I + amorphous DMSO amorphous

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1-7. (canceled)
 8. A salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acidselected from the group consisting of Na salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid; Ksalt of 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylicacid; Ca salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid;L-Arginine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl(cyclopropanecarboxylic acid;D-Arginine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid; andL-Lysine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid. 9.(canceled)
 10. A pharmaceutical composition, comprising a substantiallypure salt according to claim 8, and a pharmaceutically acceptablecarrier.
 11. (canceled)
 12. A method of the treatment or prophylaxis ofAlzheimer's Disease, comprising administering to a subject in needthereof an effective amount of a salt according to claim
 8. 13. Apharmaceutical composition according to claim 10, which comprises Nasalt of 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylicacid.
 14. A pharmaceutical composition according to claim 10, whichcomprises K salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid. 15.A pharmaceutical composition according to claim 10, which comprises Casalt of 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylicacid.
 16. A pharmaceutical composition according to claim 10, whichcomprises L-Arginine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid. 17.A pharmaceutical composition according to claim 10, which comprisesD-Arginine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid. 18.A pharmaceutical composition according to claim 10, which comprisesL-Lysine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid. 19.A method to claim 12, which comprises administering Na salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid. 20.A method to claim 12, which comprises administering K salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid. 21.A method to claim 12, which comprises administering Ca salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid. 22.A method to claim 12, which comprises administering L-Arginine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid. 23.A method to claim 12, which comprises administering D-Arginine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid. 24.A method to claim 12, which comprises administering L-Lysine salt of1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid.